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Hypertonic saline (salt water with at least 3% salt) nebulised as a fine mist through a mask or mouthpiece for cystic fibrosis

Review question

We reviewed the evidence for treatment with nebulised hypertonic saline compared to placebo or other agents for improving mucus clearance in the lungs of people with cystic fibrosis (CF).

Background

People with CF produce large amounts of thick mucus which is difficult to clear and blocks up their airways. Chest physiotherapy or medication e.g. hypertonic saline, or both combined, are used to try and clear this mucus from the airways. Hypertonic saline is water with a concentration of 3% to 7% salt and is inhaled as a fine mist. This is an update of an earlier review.

Search date

The evidence is current to: 08 August 2018.

Trial characteristics

We included 17 trials with 966 participants with CF aged between 4 months and 63 years. Eleven trials compared hypertonic saline to isotonic saline (water with 0.12 to 0.9% salt (described as placebo (a dummy treatment)); one trial compared isotonic saline and voluntary cough to hypertonic saline or mannitol 300 mg; three trials compared hypertonic saline to rhDNase (Pulmozyme®); one trial compared hypertonic saline to amiloride; and one trial compared hypertonic saline to Mistabron®. Trials assessed different concentrations of hypertonic saline with different nebulisers and different treatment schedules; the most common treatment was twice-daily 7% hypertonic saline and the most common nebuliser was ultrasonic. Most trials treated people with a bronchodilator to widen the airways before giving the hypertonic saline.

Key results

Hypertonic saline 3% to 7% versus placebo

In three trials (225 people) lung function improved after four weeks, but only one trial (164 people) reported results after 48 weeks, and showed no difference in lung function. No deaths were reported. One adult trial reported fewer exacerbations needing antibiotics with hypertonic saline than with placebo, but a trial in children found no difference in this outcome. There was not enough information to properly assess adverse events such as cough, chest tightness, tonsillitis and vomiting. In four trials (80 participants) sputum clearance was better with hypertonic saline.

One trial in 132 adults with an exacerbation reported uncertain effects of hypertonic saline on short-term lung function and the time to the next exacerbation after discharge from hospital. No deaths were reported. Side effects such as cough and wheeze were reported, but there were no serious side effects.

Hypertonic saline versus mucus mobilising treatments

We could analyse data from two of the three trials comparing hypertonic saline to rhDNase (61 participants). In one trial there was no difference in lung function at three weeks, but the second reported rhDNase led to a greater increase in lung function at 12 weeks in people with moderate to severe disease. One trial (47 participants) reported no difference in the number of exacerbations, but there was increased cough with hypertonic saline compared to rhDNase. There was not enough information to assess other side effects. No deaths were reported.

One trial (12 participants) compared hypertonic saline to amiloride and one (n = 29) to Mistabron®. Neither trial found a difference between treatments in any measures of sputum clearance. The trial comparing hypertonic saline and Mistabron® also reported no differences in how many antibiotic courses were prescribed or in side effects.

The trial comparing hypertonic saline to mannitol (12 participants) did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' .

Quality of the evidence

The risks of bias due to people not being randomly chosen to receive different treatments or due to not all results being reported range from low to unclear, but there is a high risk that people knew which treatment they were receiving in half the trials as they could taste the difference between the solutions.

The quality of the evidence was low or very low. Besides the risks of bias, the main problems were the small numbers of participants in trials combined with a wide variation in results; also, some trials limited participants to those who could tolerate hypertonic saline or to certain age groups.

Authors' conclusions:

Regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (very low-quality evidence from three trials), but this was not sustained at 48 weeks (low-quality evidence from one trial). The review did show that nebulised hypertonic saline reduced the frequency of pulmonary exacerbations (although we found insufficient evidence for this outcome in children under six years of age) and may have a small effect on improvement in quality of life in adults.

Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function at three months; qualifying this we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rHDNase, there were no differences seen in any of the secondary outcomes.

Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the quality of the evidence ranged from very low to at best moderate, according to the GRADE criteria.

Read the full abstract...

Background:

Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.

Objectives:

To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance.

Randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).

Data collection and analysis:

Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE.

Main results:

A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions.

Hypertonic saline 3% to 7% versus placebo

At four weeks, we found very low-quality evidence from three placebo-controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice-daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV1) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI -2.72 to 7.34) (low-quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low-quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low-quality evidence). Four trials (n = 80) found very low-quality evidence that sputum clearance was better with hypertonic saline.

A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short-term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post-discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low-quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low-quality evidence).

Hypertonic saline versus mucus mobilising treatments

Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three-week trial (14 participants) to determine the effects of hypertonic saline on FEV1 % predicted, mean difference (MD) 1.60% (95% CI -7.96 to 11.16) (very low-quality evidence). In the second trial, rhDNase led to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low-quality evidence). One cross-over trial (47 participants) reported 15 exacerbations during treatment with hypertonic saline and 18 exacerbations in the rhDNase group (low-quality evidence). Increased cough was reported in 13 participants using hypertonic saline and 17 on daily rhDNase in one cross-over trial of 47 people (low-quality evidence). There was insufficient evidence to assess rates of other adverse events reported. No deaths were reported.

One trial (12 participants) compared hypertonic saline to amiloride and one (29 participants) to sodium-2-mercaptoethane sulphonate. Neither trial found a difference between treatments in any measures of sputum clearance; additionally the comparison of hypertonic saline and sodium-2-mercaptoethane sulphonate reported no differences in courses of antibiotics or adverse events (very low-quality evidence).

One trial (12 participants) compared hypertonic saline to mannitol but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-quality evidence).